CHL1 (Close Homolog of L1) is an integrin-interacting cell recognition molecule related to the L1 cell adhesion molecule with a potential role in area-specific development of the neocortex. Mutation of the CHL1 gene (CALL) in humans is associated with the 3p-syndrome of mental retardation. CHL1 is expressed in a high caudal to low rostral gradient in cortical precursors during radial migration and in differentiating pyramidal neurons. Preliminary results show CHL1 knockout mice exhibit area- and lamina-specific abnormalities in radial migration and apical dendrite projection of pyramidal cells, and topographic mapping errors of thalamocortical axons. The hypothesis to be tested is that CHL1 modulates radial migration of cortical neurons in the mouse neocortex with consequences on dendrite projection and thalamocortical mapping. Aims are: (1) To define the area- and lamina-specific distribution of cortical neurons and their dendritic development in homozygous and heterozygous CHL1 knockout mice and to assess the interaction of CHL1 with L1 in double mutant mice. A role for CHL1 in Semaphorin 3A-induced dendritic projection and branching of pyramidal neurons will be studied in cortical slices. (2) To determine the cellular mechanism of CHL1 in radial migration of cortical neurons in the posterior neocortex by BrdU labeling in vivo and in brain slice assays by time lapse videomicroscopy. (3) To investigate the molecular mechanism of CHL1 in intracellular signaling through intermediates (Src, Rac, Pak, ERK1,2) important for adhesion dynamics. (4) To identify topographic mapping defects in the thalamocortical projection of CHL1-/- mice by axon tracing in vivo and to analyze CHL1 function in thalamic axon guidance by axon tracing in embryos and a novel telencephalic whole mount assay. This investigation can reveal new molecular determinants and novel mechanisms governing cortical area development and provide insight into the pathology associated with mental retardation.